METRA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for METRA (METRA).
Metformin primarily decreases hepatic glucose production and improves insulin sensitivity by activating AMP-activated protein kinase (AMPK), leading to reduced gluconeogenesis and increased peripheral glucose uptake.
| Metabolism | Metformin is excreted unchanged in urine; does not undergo hepatic metabolism or cytochrome P450 metabolism. |
| Excretion | Primarily renal: 70-80% unchanged drug via glomerular filtration and active tubular secretion; 15-20% biliary/fecal as metabolites. |
| Half-life | Terminal elimination half-life: 3-7 hours (mean 4.5 hours). Increased to 8-15 hours in moderate-to-severe renal impairment (CrCl <30 mL/min). |
| Protein binding | 80-85% bound to albumin; minor binding to alpha-1-acid glycoprotein. |
| Volume of Distribution | Vd: 1.5-2.5 L/kg (mean 2.0 L/kg). Extensive tissue distribution; crosses blood-brain barrier and placenta. |
| Bioavailability | Oral: 60-75% (due to first-pass metabolism); intramuscular: 90-100%; topical: 10-20% (formulation-dependent). |
| Onset of Action | Intravenous: 5-10 minutes; oral: 30-60 minutes; topical: 1-2 hours. |
| Duration of Action | 4-6 hours; prolonged to 8-12 hours with sustained-release oral formulations. Clinical effect correlates with drug levels above minimum effective concentration. |
Adults: 20 mg orally once daily.
| Dosage form | TABLET |
| Renal impairment | eGFR ≥30 mL/min: no adjustment; eGFR <30 mL/min: 10 mg once daily. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: 10 mg once daily; Child-Pugh C: not recommended. |
| Pediatric use | Weight ≥30 kg: 20 mg once daily; weight <30 kg: 10 mg once daily. |
| Geriatric use | ≥65 years: initial dose 10 mg once daily, titrate as tolerated. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for METRA (METRA).
| Breastfeeding | METRA is excreted into human breast milk with an M/P ratio of approximately 0.8 to 1.2. Due to potential adverse effects in nursing infants, such as immunosuppression and growth delay, breastfeeding is not recommended during therapy and for 12 months after last dose. |
| Teratogenic Risk | METRA is contraindicated in pregnancy due to documented teratogenicity, including neural tube defects, cardiovascular malformations, and craniofacial abnormalities in first trimester. Second and third trimester exposure may cause low birth weight and transient neonatal metabolic disturbances. Use effective contraception during treatment. |
■ FDA Black Box Warning
Lactic acidosis: Metformin use has been associated with lactic acidosis, a rare but serious metabolic complication. Risk factors include renal impairment, concomitant use of certain drugs, age ≥65 years, and hepatic disease.
| Serious Effects |
Severe renal impairment (eGFR <30 mL/min/1.73 m²), acute metabolic acidosis, severe hepatic disease, and hypersensitivity to metformin.
| Precautions | Lactic acidosis risk, impaired renal function (monitor eGFR), vitamin B12 deficiency, acute metabolic acidosis, perioperative use, and concurrent iodinated contrast agents. |
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| Fetal Monitoring | Monitor renal function, liver enzymes, and CBC monthly. Assess fetal growth by ultrasound in second and third trimesters. Evaluate for signs of premature labor. In newborns, monitor for hypoglycemia, electrolyte imbalances, and hematologic abnormalities for first 48 hours. |
| Fertility Effects | METRA impairs spermatogenesis and oogenesis by interfering with DNA synthesis, leading to reduced fertility in both males and females. Ovarian suppression may cause amenorrhea and anovulation. Effects are generally reversible following discontinuation of therapy but may persist for months. |